In this project a group of clinical, basic and social scientists including pediatricians, internists, hematologists, biochemicsts, biophysicists, geneticists, immunologists biostatisticians, sociologists, social workers, and clinical psychologists, will investigte aspects of sickle cell disease in three basic areas. The first is basic research relative to: a) the sickling process at the cellular level including the structure and kinetics of ISC's, and alternatives in cell membrane structure and composition and function accompanying sickling; b) the control of the synthesis of fetal hemoglobin; c) the feasibility of introducing noirmal beta-globin genes into hematopoietic stem cells; and d) the identification and testing of new pharmacologic agents which have membrane expansiona nd calmodulin inhibit from properties and thereby may be effective antisickling agents. The second are of research is clinical and includes efforts: a) to identify factors which affect the severity of sickle cell anemia including nutritional factors (zinc), the levels of A2 an fetal hemoglobin, the types of ISC, knowledge about the disease and the childs' and parents' behavior when the child has a pain attack; b) to test new therapeutic approaches including, the use of zinc to improve growth and sexual development, the use of an iron chelator to reduce the risk of iron cytopathology from chronic transfusions; and c) to reduce the incidence of death from pneumococcal infection through a better understanding of when to administer the pneumococcal vaccine. The third area of research involves the service programs and will among their objectives a) determine the effectiveness of nurse practitioners as primary care providers; b) determine the personal factors associated with employment success; and c) determine the effectiveness of our sickle cell trait counseling program and the relationship between counselors' performance and the ability of counselees to grasp the information being transferred.